The abuse of amphetamine and its congeners continues to plaque society; indeed, some indicators suggest that amphetamine abuse is increasing. Significant advances have been made in characterizing the effects of methamphetamine (METH) on brain neurochemistry. Large doses of METH decrease activity of the brain biogenic amine synthetic enzymes, tyrosine hydroxylase and tryptophan hydroxylase, as well as concentrations of dopamine and 5-hydroxytryptamine and their metabolites. These changes are accompanied by dramatic alterations in selected brain neuropeptide systems. Although significant progress has been made, additional studies are indicated to elucidate the mechanism(s) responsible for these effects. Results from preliminary studies strongly that glutamate and calcium contribute to METH-medicated neurochemical alterations. Because manipulation of these systems may lead to important new treatments for amphetamine abuse and toxicity, the role of glutamate and calcium in METH- induced effects will be investigated. The significance of the substantial neuropeptide changes observed after METH will be extensively studied. The increasing public health problem of drug abuse during pregnancy prompted the proposed study to determine whether the marked neurochemical changes observed in adult rats also occur in the offspring exposed in utero to METH. Since the incidence of smoking crystalline METH appears to be increasing, especially in the western United States, neurochemical responses observed when METH is administration. The inhalation will be compared with those occurring after parenteral administration. The procedures employed to determine the activity of biosynthetic enzymes, concentrations of neurotransmitters and their metabolites, neuropeptide levels and drug concentrations in various brain regions are techniques which are routinely utilized in our laboratories. The results of these studies will provide additional information about the interrelationships between neuropeptide, biogenic amine and excitatory amino acid systems within the brain. Moreover, a better understanding of the mechanisms responsible for the neurochemical changes observed after METH will hopefully lead to improved treatment strategies for amphetamine abuse and toxicity. These findings will also hopefully provide improved understanding and better therapy for neurological dysfunctions related to parkinsonism, brain ischemia and psychotic illness.